Polypeptides are susceptible to denaturation or enzymatic degradation in the blood, liver or kidney. Accordingly, polypeptides typically have short circulatory half-lives of several hours. Because of their low stability, peptide drugs are usually delivered in a sustained frequency so as to maintain an effective plasma concentration of the active peptide. Moreover, since peptide drugs are usually administrated by infusion, frequent injection of peptide drugs cause considerable discomfort to a subject. Thus, there is a need for technologies that will prolong the half-lives of therapeutic polypeptides while maintaining a high pharmacological efficacy thereof. Such desirous peptide drugs should also meet the requirements of enhanced serum stability, high activity and a low probability of inducing an undesired immune response when injected into a subject.
Unfavorable pharmacokinetics, such as a short serum half-life, can prevent the pharmaceutical development of many otherwise promising drug candidates. Serum half-life is an empirical characteristic of a molecule, and must be determined experimentally for each new potential drug. For example, with lower molecular weight polypeptide drugs, physiological clearance mechanisms such as renal filtration can make the maintenance of therapeutic levels of a drug unfeasible because of cost or frequency of the required dosing regimen. Conversely, a long serum half-life is undesirable where a drug or its metabolites have toxic side effects.
Interferons (IFNs) are a family of functionally related cytokines that exhibit antiviral, antiproliferative and immunomodulatory activities. They are divided into two groups, designated type I and type II IFNs. The type I IFNs include the IFN-α family (e.g. IFN-α2a, IFN-α2b, IFN-αn3, and IFN-αcon-1), IFN-β and IFN-omega. They are all structurally related and compete for the same cell surface receptor. Type I interferons are produced in many cell types upon infection by a variety of viruses. IFN-γ is the sole member of the type II IFNs. It is acid labile, binds to its own specific receptor and is produced by activated T cells and NK cells.
Type I and Type II IFNs have overlapping but clearly distinct biological activities. Type I IFNs induce antiproliferative and antiviral activity, while type II IFN-γ has weaker antiviral activity but more potent immunomodulatory properties. IFN-γ exhibits also immune functions, including macrophage activation.